influence of sex and stress exposure across the lifespan on endophenotypes of depression focus on behavior glucocorticoids and hippocampus

Neuroendocrine Science Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids and hippocampus Aarthi Raksha Gobinath, Rand Mahmoud and Liisa Ann Margaret Galea Journal Name: Frontiers in Neuroscience ISSN: 1662-453X Article type: Review Article Received on: 14 Jul 2014 Accepted on: 02 Dec 2014 Provisional PDF published on: 02 Dec 2014 www.frontiersin.org: www.frontiersin.org Citation: Gobinath AR, Mahmoud R and Galea LA(2014) Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids and hippocampus Front Neurosci 8:420 doi:10.3389/fnins.2014.00420 Copyright statement: © 2014 Gobinath, Mahmoud and Galea This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice No use, distribution or reproduction is permitted which does not comply with these terms This Provisional PDF corresponds to the article as it appeared upon acceptance, after rigorous peer-review Fully formatted PDF and full text (HTML) versions will be made available soon 1  2  3  4  5  6  7  8  Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids and hippocampus Aarthi R Gobinath1, Rand Mahmoud1, and Liisa A.M Galea1,2* Program in Neuroscience, Centre for Brain Health, 2Department of Psychology, University of British Columbia, Vancouver, BC, Canada 9  10  11  12  13  14  15  16  17  18  *Correspondence: Dr Liisa Galea University of British Columbia Department of Psychology 2136 West Mall Vancouver, BC V6T 1Z4, Canada lgalea@psych.ubc.ca 1    19  Abstract 20  21  22  23  24  25  26  27  28  29  30  31  Sex differences exist in vulnerability, symptoms and treatment of many neuropsychiatric disorders In this review we discuss both preclinical and clinical research that investigates how sex influences depression endophenotypes at the behavioral, neuroendocrine, and neural levels across the lifespan Chronic exposure to stress is a risk factor for depression and we discuss how stress during the prenatal, postnatal, and adolescent periods differentially affects males and females depending on the method of stress and metric examined Given that the integrity of the hippocampus is compromised in depression, we specifically focus on sex differences in how hippocampal plasticity is affected by stress and depression across the lifespan In addition, we examine how female physiology predisposes depression in adulthood, specifically in postpartum and perimenopausal periods Finally, we discuss the underrepresentation of women in both preclinical and clinical research and how this limits our understanding of sex differences in vulnerability, presentation, and treatment of depression 32  2    33  Introduction 34  Sex Differences in Depression 35  36  37  38  39  40  41  There are a number of sex differences in incidence, manifestation, symptoms, and treatment efficacy of neuropsychiatric disorders, however often these sex differences are ignored in the literature (Cahill 2006) Even at the cellular levels, chromosomal influences (XX or XY genotype) can have profound effects on the cellular activity of every cell in the body, including neurons (Penaloza et al., 2009; Straface et al., 2012) Thus, it is curious that such a fundamental aspect of cellular function and physiology is largely ignored when understanding the neural basis and treatment of diseases 42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60  61  62  63  64  65  66  67  68  69  70  71  72  73  Epidemiological findings consistently show a sex disparity in the lifetime prevalence of depression, with women being twice more likely to be affected (Gutierrez-Lobos et al 2002) This sex difference in prevalence is seen across cultures (Seedat et al., 2009), emerges during adolescence (Nolen-Hoeksema and Girgus, 1994), and is most apparent during the reproductive years (i.e 25-50 years; Gutierrez-Lobos et al 2002) Indeed, there is an increased incidence of depression in women during periods associated with dramatic fluctuations in gonadal hormones particularly during the postpartum and perimenopausal periods (Cohen et al., 2006, Hendrick et al, 1998) Alternatively, when the perinatal period is disturbed, males may be more vulnerable than females to develop other neuropsychiatric diseases, such as autism and schizophrenia, across the lifespan (Stevenson et al., 2000; Kent et al., 2012) Several biological and psychosocial theories have been put forth to explain the underlying cause of the sex differences in depression, but the most prominent neurobiological hypothesis emphasizes the role of gonadal hormones (Hammarstrom et al., 2009) Sex differences in depression extend beyond prevalence rates and course of illness as the symptom profile and clinical presentation differs between men and women Several studies report that women are more likely to present with comorbid anxiety disorders (Sloan et al., 2003, Keers and Aitchison, 2010) as well as atypical depression, which is associated with hypersomnia, hyperphagia, or excessive fatigue (Young et al., 1990, Silverstein 2002) Interestingly, sex is also implicated in antidepressant efficacy, with selective serotonin reuptake inhibitors (SSRIs) being more effective in alleviating symptoms in women, and tricyclic antidepressants (TCAs) being more effective in alleviating symptoms in men (Keers and Aitchison, 2010) However sex differences in antidepressant efficacy are not always seen (Parker et al., 2003; Dalla et al., 2010) As we discuss later in this review, animal studies of depression have predominantly used male subjects, and thus our understanding of what underlies this differential antidepressant efficacy is limited The available animal literature on sex-dependent antidepressant efficacy reveals mixed findings (Dalla et al., 2010); for example, some studies suggests that SSRIs are more efficacious in alleviating depressive-like behavior in female rats (Gomez et al., 2014), but others show a higher efficacy in males (Lifschytz et al., 2006) However, the latter study did not account for estrous cycle phase, which may affect depressivelike behavior and antidepressant efficacy Together these data point to a critical role of sex and gonadal hormones on depression risk, manifestation, and treatment Stress and HPA involvement in depression 74  75  Exposure to chronic stress is tightly linked to the development of depression (reviewed in Tennant 2002) The hypothalamic-pituitary-adrenal (HPA) axis, a major neuroendocrine stress 3    76  77  78  79  80  81  82  83  84  85  86  87  88  89  90  91  92  93  94  95  96  97  98  99  100  101  102  system (reviewed in Ulrich-Lai and Herman, 2009) exhibits a number of changes in at least a subpopulation of depressed patients, with key features being elevated basal cortisol levels, disrupted diurnal cortisol secretion patterns, and HPA negative feedback dysregulation (Parker et al., 2003; Ising et al., 2007; Schule 2007; Stetler and Miller, 2011) The HPA negative feedback system can be tested with the administration of dexamethasone, a synthetic glucocorticoid that suppresses cortisol secretion in healthy but not depressed individuals (Carroll, Martin, and Davies, 1968; Ising et al., 2007) Chronic treatment with antidepressants can restore the negative feedback function of the HPA axis that either slightly precedes or is coincident with the alleviation of depressive symptoms (Ising et al., 2007) Interestingly, antidepressant effects to normalize HPA negative feedback dysregulation are more tied to remission in women than in men (Binder et al., 2009) Many animal models of depression emphasize the role of stress (reviewed in Yan et al., 2010), and HPA axis dysregulation is used as a measure of a depressivelike endophenotype in such models (Christiansen et al., 2012) Different types of stressors can profoundly influence the effects on depressive phenotypes with generally unpredictable psychological stressors more likely to promote depressive-like behaviors than predictable stressors, which can sometimes provide resilience to depressive-like behaviors (reviewed in McEwen 2000; reviewed in McEwen 2002; Suo et al., 2013; Parihar et al., 2011) Furthermore greater allostatic load is associated with more profound effects on depression and the hippocampus (reviewed in McEwen 2000; reviewed in McEwen 2002) More profound HPA axis dysregulation as a result of chronic stress is seen in female rats when compared to males, marked by larger elevations in corticosterone (CORT), the main glucocorticoid in rodents (Dalla et al 2005) These findings indicate that HPA dysregulation is seen in both humans and rodents, and this effect may be more profound in females Moreover, females have naturally higher levels of CORT than males (reviewed in Viau, 2002) and this may contribute to higher incidence of depression in females It should be noted that other stress hormones such as corticotrophin releasing hormone and adrenocorticotropic hormone have been implicated in depression but are beyond the scope of this review and are reviewed elsewhere (e.g Valentino et al., 2012) 103  The hippocampus and depression 104  105  106  107  108  109  110  111  112  113  114  The hippocampus is a highly plastic structure that is sensitive to the effects of stress and sex hormones, both of which are closely linked to depression A meta-analysis confirmed that untreated depression is associated with a smaller volume of the hippocampus in depressed patients that have been depressed for at least years (McKinnon et al., 2009) The smaller hippocampus associated with depression is an effect that is more prominent in men than women (Frodl et al., 2002) and in middle-aged and older patients (McKinnon et al., 2009) Furthermore, chronic antidepressant exposure appears to increase hippocampal volume in treatment-responding women more so than men (Vakili et al., 2000; reviewed in Lorenzetti et al., 2009) The hippocampus is a highly plastic structure in adulthood (reviewed in Leuner and Gould, 2010), and hippocampal volume fluctuations may be due to changes in neurogenesis, neuropil, and/or apoptosis Postmortem studies reveal decreased cell proliferation in the dentate gyrus of the hippocampus of 4    115  116  117  118  119  120  121  122  123  124  125  126  127  128  129  130  depressed patients (Boldrini et al., 2012) Similarly, hippocampal neurogenesis is reduced in every animal model of depression examined so far (Jaako-Movits et al., 2006; Green and Galea, 2008; Bessa et al., 2009; Brummelte et al 2010) Chronic but not acute antidepressant treatment restores the depression-model induced decrease in neurogenesis (Green and Galea, 2008; Bessa et al 2009) Intriguingly, depressed women taking antidepressants have a larger ratio of immature to mature neurons in the hippocampus (an increase in neurogenesis) compared to controls, but the same relationship was not seen in men (Epp et al., 2013) These findings are consistent with the findings that women taking antidepressants show increased hippocampal volume compared to men (Vakili et al., 2000) Furthermore, the effect of antidepressants to induce neurogenesis in the hippocampus is not seen in older depressed patients (Lucassen et al., 2010; Epp et al., 2013), which may be consistent with the lack of efficacy of antidepressants to alleviate depression in older patients (Lenze et al., 2008) Neuropsychological evidence also suggests functional hippocampal impairment in depression, further supporting the role of the hippocampus in the pathophysiology of the disease For example, a meta-analysis of 726 patients with depression showed neurocognitive impairment, most severely in episodic, declarative memory (Zakzanis, Leach, and Kaplan, 1998), a hippocampal-dependent memory system 131  132  133  134  135  136  137  138  139  140  141  142  143  144  145  146  147  148  149  150  151  Animal models also show sex-dependent alterations in hippocampal plasticity as a result of chronic stress or chronic corticosterone treatment Interestingly, chronic footshock stress reduced newly produced cells in the dentate gyrus of individually-housed young adult male rats, but increased new cells in young adult female rats (Westenbroek, et al., 2004) Chronic restraint stress reduces neuropil (branch points and dendritic length) in the apical dendrites of CA3 pyramidal cells of the hippocampus in male rats but in the basal dendrites of CA3 pyramidal cells in female rats (Galea et al., 1997) Chronic CORT treatment reduced the density of immature neurons in the dorsal and ventral hippocampus of young adult male rats, but only the ventral hippocampus in young adult female rats (Brummelte and Galea 2010) While some researchers suggest that females are less susceptible to the damaging effects of chronic stress than males, this is very much dependent on the nature, duration of the stressor and the background hormonal environment of the female, with generally higher levels of ovarian hormones contributing to fewer damaging effects of stress (Shors, Chua, and Falduto, 2001; Conrad et al., 2012) Nonetheless these findings suggest that more research is needed to examine how stress alters plasticity in the hippocampus, how these changes in neuroplasticity translate into behavior and disease susceptibility, and how ovarian hormones contribute to this process Further, stress and ovarian hormones can certainly influence risk for depression and plasticity of other limbic areas, such as the prefrontal cortex, and neurotransmitters, such as serotonin and dopamine, but this is beyond the scope of this review and are addressed elsewhere (e.g Valentino et al., 2012; Goldstein et al., 2014) 152  153  Anhedonia, i.e the loss of pleasure or interest in previously pleasurable experiences, is one of the core symptoms of clinical depression Not surprisingly, many animal models of Examining depressive-like endophenotypes in animal models 5    154  155  156  157  158  159  160  161  162  163  164  165  166  167  168  169  170  depression focus on modeling anhedonia as a central behavioral endophenotype, typically by measuring the consumption of or preference for sucrose solutions While reductions in the hedonic value of sucrose as a result of chronic unpredictable stress is seen in both male and female rats, the effect is more profound in male rats (Grippo et al., 2005; Dalla et al 2005, 2008; Kamper et al 2009) Because sucrose consumption/preference tests were first developed in male rodents, and because baseline sucrose consumption in females may fluctuate with the estrous cycle (Clarke and Ossenkopp, 1998), it may not be an ideal model of anhedonia in female rodents On the other hand, other stress-induced depressive-like behaviors are more evident in female rats For example, female rats show more despair-like behavior (immobility) on the forced swim test following chronic mild stress (Sachs, Ni, and Caron, 2014) but not following chronic CORT treatment (Kalynchuk et al., 2004), an effect that may be related to sex differences in basal CORT levels (reviewed in Viau, 2002) As mentioned earlier, there are also reported sex differences in the symptoms of depression and in the prevalence of comorbid disorders; women are more likely to present with co-morbid anxiety and somatic complaints, whereas men are more likely to present with co-morbid alcohol and substance abuse (Marcus et al., 2008) Clearly, more clinical and preclinical research is needed to examine sex differences in the symptoms, and in the treatment alleviation of certain symptoms of depression 171  172  173  174  175  176  177  178  179  The current article explores how adverse events present during developmental windows such as the prenatal period, the early postnatal period, and adolescence, are linked to increased vulnerability to neuropsychiatric disorders in adulthood Many sex differences in the brain are programmed early in life (Paus 2010) It perhaps is not surprising then that the sex differences associated with neuropsychiatric disorders also have a developmental component The following sections will outline how prenatal, postnatal, adolescent or adult perturbations in stress or excessive stress hormones influence vulnerability to develop depression in both humans and animal models with a special emphasis on the behavioral analysis, HPA axis modulation, and neuroplasticity in the hippocampus 180  Prenatal Manipulations & Vulnerability to Depression 181  182  183  184  185  186  187  188  189  190  191  Prenatal stress limits fetal growth and gestational length (reviewed in Seckl and Holmes, 2007), and is consequently associated with an increased risk for depression, anxiety, schizophrenia, and more recently autism (reviewed in Bale et al., 2010; Baron-Cohen et al., 2014) During gestation, the placental enzyme 11β-hydroxysteroid dehydrogenase type II inactivates excessive levels of maternal or exogenous cortisol to protect the fetus from high cortisol However there are sex differences in the response of this placental enzyme to stress exposure which could contribute to which sex is more vulnerable to excessive maternal stress (reviewed in Clifton 2010) For example, the female, but not male, placenta exhibits an increase in 11β-hydroxysteroid dehydrogenase type II expression in response to prenatal exposure to betamethasone (a synthetic glucocorticoid) prior to preterm delivery (Stark, Wright, and Clifton 2009) Although seemingly contradictory to the general pattern that females are more vulnerable 6    192  193  194  195  196  197  198  199  to depression than males, this finding is consistent with findings that males are more vulnerable to neurodevelopmental disorders that can be triggered during gestation, such as autism, and poor outcome after preterm birth (Stevenson et al., 2000; Kent et al., 2012) Thus, the developmental timing of stress exposure may play a pivotal role in which sex is more likely to develop depression and the reader is directed to excellent reviews on the subject (Andersen 2003; Teicher et al., 2003; Brenhouse and Andersen, 2011) Further research investigating how sex differences in placental function mediate developmental outcome will provide a better understanding of why males are more vulnerable to the effects of prenatal stress than females 200  201  202  203  204  205  206  207  208  Prenatal stress affects depressive behavior Gestational stress can contribute to the development of mood disorders in the mother during pregnancy (Lancaster et al., 2010) Depression during pregnancy in the mother increased emotional responses in infant boys, but not girls (Gerardin et al., 2011) and increased risk for depression in adolescence (Pawlby et al 2009; Pearson et al 2013) Furthermore, maternal anxiety during pregnancy is associated with a greater risk for depressive symptoms in adolescent girls (Van Den Bergh et al 2008) and a greater risk for attention deficits in young and adolescent boys (Van Den Bergh et al 2006; Loomans et al 2011) Together, these studies suggest that maternal mood during gestation may differentially affect behavioral outcome in boys and girls 209  210  211  212  213  214  215  216  217  218  219  220  221  222  223  224  225  226  227  228  229  230  Animal models of depression that induce prenatal stress have been used to examine how early life perturbations differentially affect male and female offspring Generally these animal models involve exposing the pregnant dam to predictable or unpredictable stress (reviewed in Weinstock 2008) Despite the fact that clinical research points to strong associations between prenatal stress and likelihood to develop depression, preclinical research has yielded mixed results However it should be noted that the third trimester equivalent in rodents is the first week postnatal and thus one reason why there may be differences between human and animal studies is timing of ‘trimester’ in different species (Kleiber et al., 2014) Timing of stress onset plays a critical role in how it affects offspring depressive-like behavior For example, one study found that prenatal stress increased depressive like behavior (increased immobility in the forced swim test) of adult male mice only when stress occurred during the first week of gestation but not during mid- or late gestation (Mueller and Bale, 2008) which would be akin to the first versus second trimester However, others have shown that prenatal restraint stress during the last week of gestation (akin to late in the second trimester) increased depressive-like behavior (increased immobility in the forced swim test) in adult males and females, although in males it is only seen when restraint occurs three times per day during the last week of gestation (Alonso et al., 1991; Morley-Fletcher et al., 2003; Szymańska, et al., 2009; Van den Hove et al., 2014) Age of offspring at behavior testing is also critical as prenatal stress had the opposite effect on depressive-like behavior (decreased immobility in the forced swim test) in pre-pubertal (P33; Schroeder, Sultany, and Weller, 2013) and adolescent male and female rats (Rayen et al., 2011) Alternatively, direct administration of CORT to the dam during days 10-20 of gestation (equivalent to second trimester) increased depressive-like behavior (increased immobility in the 7    231  232  233  234  235  236  237  forced swim test) for both adolescent male and female rats (Brummelte, Lieblich, and Galea, 2012) Ultimately, duration of prenatal stress, frequency of stress exposure, timing of prenatal stress, type of stressor employed, species, and age of offspring at testing influence depressivelike behavior of the offspring (reviewed in Huiznik, Mulder, and Buitelaar, 2004; reviewed in Weinstock 2011) Additional research addressing how these differences in methodologies influence offspring outcome will be valuable for understanding how prenatal factors influence vulnerability to depression in males and females 238  239  240  241  242  243  244  245  246  247  248  249  250  251  Prenatal stress affects development of HPA axis Prenatal stress can have variable programming effects on the HPA axis of offspring depending on sex, the paradigm of prenatal stress and the part of the HPA axis (basal, stress peak, stress recovery) analyzed (Barbazanges et al., 1996; Zagron and Weinstock, 2006) For instance, prenatal stress for even one week of gestation can result in prolonged CORT recovery after acute stress in adult female but not in adult male rats (Weinstock et al., 1992; McCormick et al., 1995) However, after more intense prenatal stress (stress three times per day throughout gestation and equivalent to first two trimesters), both male and female rats displayed prolonged CORT recovery after restraint (Maccari et al., 1995; Morley-Fletcher et al., 2003) and disrupted diurnal CORT rhythm (Koehl et al., 1999) Alternatively, social defeat stress during the last week of gestation (equivalent to second trimester) exaggerated the peak CORT response after restraint in both adult male and female rats (Brunton and Russell, 2010) These findings suggest that more intense paradigms of prenatal stress are capable of reprogramming the male HPA axis whereas females seem to be sensitive to milder forms of prenatal stress 252  253  254  255  256  257  258  259  260  In clinical studies, prenatal stress has been associated with HPA axis dysregulation in infants, adolescents, and adults (reviewed in Glover, O’Connor, and O’Donnell 2010) However, there are limited studies directly assessing how sex mediates the effects of prenatal stress on the development of the HPA axis Both maternal prenatal anxiety and prenatal exposure to synthetic glucocorticoids (either dexamethasone or betamethasone) increased stress reactivity in girls only (de Bruijn et al., 2009; Alexander et al., 2012) However, whether HPA axis dysregulation persists in girls or whether it emerges later on in boys remains unknown Future clinical studies directly analyzing how sex mediates the relationship between prenatal stress and development of HPA axis are necessary to address this gap 261  262  263  264  265  266  267  268  Prenatal stress affects hippocampal plasticity Prenatal stress persistently decreased cell proliferation in the hippocampus of juvenile, adolescent, adult, and aged male rodents (Lemaire et al., 2000; Mandyam et al., 2008; Rayen et al., 2011; Belnoue et al., 2013) and in prepubescent rhesus monkeys (2-2.5 years old; Coe et al., 2003) The prenatal stress-induced decrease in cell proliferation is more prominent in the ventral hippocampus (Zuena et al., 2008) and the ventral hippocampus is associated with stress and anxiety (reviewed in Fanselow and Dong, 2010) more so than the dorsal hippocampus In contrast, the effect of prenatal stress on hippocampal cell proliferation in female offspring is more complicated Prenatal stress decreased 8    269  270  271  272  273  274  275  276  277  278  279  280  281  282  283  284  285  286  hippocampal cell proliferation in adolescent female rats (Rayen et al., 2011) but had variable effects in adult females Prenatal stress diminished cell proliferation in adult (5 months old) female rats (Mandyam et al., 2008) and in aged (2 year old) females (Koehl et al 2009) but the later study did not see the same effect in younger adult female offspring Although both studies employed the same prenatal stress paradigm, there were differences in onset of prenatal stress (gestational day 14 or 15) as well as breeding (shipped pregnant versus breeding in house) that may explain this conflict (Laroche et al., 2009) Prenatal stress diminished number of immature neurons (doublecortin expressing) in adolescent male and female rats (Rayen et al., 2011) and decreased neurogenesis in adult male rodents (Lemaire et al., 2000; Belnoue et al., 2013) Prenatal stress affects other aspects of hippocampal morphology as well as other regions of limbic system and are reviewed elsewhere (e.g Charil et al., 2010, Weinstock 2011) In nonhuman primates, there are known effects of prenatal excessive glucocorticoids to show damage to different areas of the hippocampus (reduction in volume) into middle age (Uno et al., 1994) In humans, one study found that prenatal stress diminished use of hippocampal-dependent strategies in a spatial task (Schwabe, Bohbot, and Wolf, 2012) However, whether these effects are paralleled in hippocampal volume, related to risk for depression, or differentially affected by sex remain unknown and likely need to be taken into account to fully understand the effects of prenatal and postnatal adversity on the hippocampus in humans (Frodl and O’Keane, 2013) 287  288  289  290  291  292  293  294  295  296  297  298  While there has been robust evidence from preclinical and clinical studies that prenatal stress negatively affects offspring outcome, prenatal stress can also diminish quality of maternal care (Champagne and Meaney, 2006) and even serve as a model of postpartum depression (PPD; Smith et al., 2004; Leuner et al., 2014) Thus, studies that employ prenatal stress paradigms essentially result in a mix of prenatal and postnatal adversity, obscuring the degree to which poor functional outcome can be attributed to in utero stress alone Cross-fostering of prenatally stressed with non-stressed rodent pups reverses certain behavioral and endocrine effects (Barros et al., 2006; Del Cerro et al., 2010; Perez-Laso et al., 2013) In humans, studies have found that some of the negative effects of prenatal stress on child outcome is mediated by the early postnatal environment, such as presence of postpartum mood disorders or poor maternal care (Kaplan, Evans, and Monk, 2008; Bergman et al., 2010; Rice et al., 2010) These studies highlight the prenatal and postnatal environments as potent mediators in offspring development 299  Postnatal Manipulations & Vulnerability to Depression 300  301  302  303  304  305  306  Several forms of postnatal early life stress, such as sexual, physical, or emotional abuse as well as parental loss, neglect, or mental illness constitute increased risk for adult mood and anxiety disorders (Famularo, Kinscherff, and Fenton, 1992; 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Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids and hippocampus Aarthi R Gobinath1, Rand Mahmoud1, and Liisa... duration of prenatal stress, frequency of stress exposure, timing of prenatal stress, type of stressor employed, species, and age of offspring at testing influence depressivelike behavior of the offspring... depressivelike behavior and antidepressant efficacy Together these data point to a critical role of sex and gonadal hormones on depression risk, manifestation, and treatment Stress and HPA involvement in depression